This application claims priority from German Application No. 19732839.3, filed on Jul. 30, 1997, the subject matter of which is hereby incorporated herein by reference.
The invention relates to a method of isolating 1-[N2-((S)-ethoxycarbonyl)-3-phenylpropyl)-N6-trifluoroacetyl]-L-lysyl-L-proline (LPE, compound I). 
N-substituted amino acids of this type are valuable intermediate products for the production of inhibitors of angiotensin-converting enzyme (ACE), which act as regulators of blood pressure. The compound of formula (I) is the direct intermediate product for 1-[N2-((S)-carboxy)-3-phenylpropyl)]-L-lysyl-L-proline (Lisinopril II), which exhibits superb therapeutic results in combating high blood pressure (Zestril(copyright), Coric(copyright), Prinivil(copyright)).
Compound (I) is obtained according to the state of the art by the reductive amination of 2-oxo-4-phenyl-ethyl butyrate with the dipeptide Lys (Tfa)-Pro. 
Such a method is described in the J. Org. Chem. 1988, 53, pp. 836-844. According thereto, compound (I) is obtained in a yield of 42% by basic extraction of the raw reaction solution, a subsequent extraction of the product in methylene chloride at pH 4.6 and, after a change of solvent, crystallization from methyl-tert.butyl ether, cyclohexane.
EP 05 23 449 concerns the synthesis of compound (I) obtained according to example 3 with a yield of 60%. The workup of the raw reaction solution obtained according to this method contains, in addition to the basic and an acidic extraction step with 1,1,1-trichloroethane, a crystallization from methyl-tert.-butyl ether.
In principle, other methods for producing compound (I) are also known which are not based on reductive amination but are less advantageous (EP 0 336 368 A2). The aqueous product phase is extracted therein with methylene chloride. However, after drying of the organic phase over sodium sulfate the solvent is again changed for crystallization in methyl-tert.-butyl ether.
The crystallization from pure methyl-tert.-butyl ether results in a crystal grain which is difficult to filter and in yields which are frequently insufficient (EP 0 645 398 A1). If compound (I) is allowed to crystallize out of solutions with a high concentration an additional recrystallization becomes necessary. The addition of cyclohexane (J. Org. Chem., 1988, 53, pp. 836-844) during the crystallization for increasing the yield is also described. However, there is the danger of a separation as oil, which makes it much more difficult to isolate the product, not only on an industrial scale.
EP 0 645 398 A1 extensively examines the possibility of the crystallization of compound (I) from various solvents or solvent mixtures. It is shown therein that when methyl-tert.-butyl ether or mixtures containing methyl-tert.-butyl ether are used the residual solvent content of the crystals is very great after the crystallization and residual solvent is bound in the crystal. The LPE raw material obtained in this manner is extremely difficult to dry. Long drying times which can adversely affect the product quality (formation of DKP, especially at elevated temperatures) and the tendency of the product to agglutinate makes special, expensive drying procedures necessary.
WO 95/07928 teaches a type of workup which describes an extraction with subsequent crystallization. The raw material of the LPE production is pre-cleaned in a pH range of 0-6.3, if necessary by means of several liquid/liquid extraction steps before it is crystallized out of a mixture of methyl-tert.-butyl ether and methyl cyclohexane at reduced temperatures. A solvent exchange also takes place between the extraction and the crystallization.
A disadvantage of the methods of the state of the art for working up LPE is the fact that frequently environmentally hazardous chlorinated solvents are used and the solvent must be replaced during the workup. This is difficult to achieve completely on an industrial scale and as a result of which only insufficiently defined solvent compounds can be adjusted for the crystallization. In addition, only mild temperature conditions are permitted for such solvent changes on account of the sensitivity of the product, which entails long distillation times. Moreover, the methods of the state of the art often result in crystals which are difficult to filter and much residual solvent is included therewith. Such a product requires long drying procedures which make it difficult to control caking and agglutination on an industrial scale.
In view of the state of the art indicated and discussed herein, the invention therefore has the purpose of finding a novel method for isolating LPE (I) which permits the raw material obtained from an LPE production process to be better isolated from an aqueous product phase with a simplified and more economic process, which for its part helps reduce the customary long drying times which stress the LPE (I) and more favorable crystalline properties of the precipitated material are obtained.
The invention also has the purpose of generating an end LPE material using the novel, simpler isolating methods which end material is improved over that of the state of the art with comparable drying times, especially as concerns the residual solvent content.
The invention also has the purpose of providing an improved LPE (I)
As a result of the fact that LPE (I) is extracted with a solvent or solvent mixture from an aqueous product solution of an LPE production process produced according to the method of the state of the art and that this solvent or solvent mixture is subsequently used as a main component of the solvent or solvent mixture from which the LPE (I) is crystallized, crystals of LPE distinguished by more advantageous crystalline properties are obtained by this simplified and much more economic method. The LPE generated in this manner exhibits only slight solvent inclusion after crystallization and possesses excellent filterability on account of its well-formed crystalline structure. The slight amount of included residual solvent is a reason that the previous long drying times per drying batch can be significantly reduced. The LPE produced in this manner has a byproduct content which is just as excellently low as that of the state of the art. Thus, a product which is more advantageous in comparison to the state of the art can surprisingly be produced in spite of the simplified method of extraction and crystallization of LPE, which is a reason that a more cost-effective method for the production of LPE can be made available.